Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
Oncology Reports
Join Editorial Board Propose a Special Issue
Print ISSN: 1021-335X Online ISSN: 1791-2431
Journal Cover
January-2017 Volume 37 Issue 1

Full Size Image

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
January-2017 Volume 37 Issue 1

Full Size Image

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML
Article

The importance of mitochondrial folate enzymes in human colorectal cancer

  • Authors:
    • Masaaki Miyo
    • Masamitsu Konno
    • Hugh Colvin
    • Naohiro Nishida
    • Jun Koseki
    • Koichi Kawamoto
    • Kenta Tsunekuni
    • Junichi Nishimura
    • Taishi Hata
    • Ichiro Takemasa
    • Tsunekazu Mizushima
    • Yuichiro Doki
    • Masaki Mori
    • Hideshi Ishii
  • View Affiliations / Copyright

    Affiliations: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan, Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
  • Pages: 417-425
    |
    Published online on: November 22, 2016
       https://doi.org/10.3892/or.2016.5264
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



Abstract

Folate plays a pivotal role in the one-carbon metabolism needed for methylation reactions, nucleotide synthesis, and DNA repair. Although folate metabolism was recently shown to be associated with carcinogenesis in some solid tumors, the importance of folate metabolism in colorectal cancer remains unclear. In the present investigation we found that expression of three mitochondrial folate metabolic enzymes, serine hydroxymethyl transferase (SHMT2), methylenetetrahydrofolate dehydrogenase (MTHFD2) and aldehyde dehydrogenase 1 family member L2 (ALDH1L2), were upregulated in human colorectal tumor tissues compared to normal tissues. Colorectal cancer tissue samples were obtained from 117 consecutive patients. We evaluated the expression of the enzymes with immunohistochemical analysis and determined their relevance to clinicopathological characteristics and prognosis. Rates of recurrence-free survival (RFS) and overall survival (OS) in patients with high expression of SHMT2, MTHFD2 and ALDH1L2 tended to be lower than in patients with low expression of SHMT2, MTHFD2 and ALDH1L2 (P=0.446 and P=0.337, P=0.099 and P=0.064, P=0.178 and P=0.257, respectively). Notably, the combined high expression of SHMT2, MTHFD2 and ALDH1L2 (triple high) was more highly associated with poor prognosis than the individual expression levels (RFS; P=0.004 and OS; P=0.037). A multivariate analysis showed that triple high expression was independently associated with RFS (P=0.017). These findings suggested that mitochondrial folate metabolic enzymes could provide a potential therapeutic strategy for treating colorectal cancer.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

View References

1 

Brown JM and Giaccia AJ: The unique physiology of solid tumors: Opportunities (and problems) for cancer therapy. Cancer Res. 58:1408–1416. 1998.PubMed/NCBI

2 

Daşu A, Toma-Daşu I and Karlsson M: Theoretical simulation of tumour oxygenation and results from acute and chronic hypoxia. Phys Med Biol. 48:2829–2842. 2003. View Article : Google Scholar : PubMed/NCBI

3 

Warburg O: On the origin of cancer cells. Science. 123:309–314. 1956. View Article : Google Scholar : PubMed/NCBI

4 

Choi SW and Mason JB: Folate status: Effects on pathways of colorectal carcinogenesis. J Nutr. 132:(Suppl). 2413S–2418S. 2002.PubMed/NCBI

5 

Duthie SJ and Hawdon A: DNA instability (strand breakage, uracil misincorporation, and defective repair) is increased by folic acid depletion in human lymphocytes in vitro. FASEB J. 12:1491–1497. 1998.PubMed/NCBI

6 

Widschwendter M and Jones PA: DNA methylation and breast carcinogenesis. Oncogene. 21:5462–5482. 2002. View Article : Google Scholar : PubMed/NCBI

7 

Pike ST, Rajendra R, Artzt K and Appling DR: Mitochondrial C1-tetrahydrofolate synthase (MTHFD1L) supports the flow of mitochondrial one-carbon units into the methyl cycle in embryos. J Biol Chem. 285:4612–4620. 2010. View Article : Google Scholar : PubMed/NCBI

8 

Ventrella-Lucente LF, Unnikrishnan A, Pilling AB, Patel HV, Kushwaha D, Dombkowski AA, Schmelz EM, Cabelof DC and Heydari AR: Folate deficiency provides protection against colon carcinogenesis in DNA polymerase beta haploinsufficient mice. J Biol Chem. 285:19246–19258. 2010. View Article : Google Scholar : PubMed/NCBI

9 

Jain M, Nilsson R, Sharma S, Madhusudhan N, Kitami T, Souza AL, Kafri R, Kirschner MW, Clish CB and Mootha VK: Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. Science. 336:1040–1044. 2012. View Article : Google Scholar : PubMed/NCBI

10 

Vazquez A, Tedeschi PM and Bertino JR: Overexpression of the mitochondrial folate and glycine-serine pathway: A new determinant of methotrexate selectivity in tumors. Cancer Res. 73:478–482. 2013. View Article : Google Scholar : PubMed/NCBI

11 

Liu F, Liu Y, He C, Tao L, He X, Song H and Zhang G: Increased MTHFD2 expression is associated with poor prognosis in breast cancer. Tumour Biol. 35:8685–8690. 2014. View Article : Google Scholar : PubMed/NCBI

12 

Díez-Villanueva A, Mallona I and Peinado MA: Wanderer, an interactive viewer to explore DNA methylation and gene expression data in human cancer. Epigenetics Chromatin. 8:222015. View Article : Google Scholar : PubMed/NCBI

13 

Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Sun Y, Jacobsen A, Sinha R, Larsson E, et al: Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 6:pl12013. View Article : Google Scholar : PubMed/NCBI

14 

Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, et al: The cBio cancer genomics portal: An open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2:401–404. 2012. View Article : Google Scholar : PubMed/NCBI

15 

Koseki J, Colvin H, Fukusumi T, Nishida N, Konno M, Kawamoto K, Tsunekuni K, Matsui H, Doki Y, Mori M, et al: Mathematical analysis predicts imbalanced IDH1/2 expression associates with 2-HG-inactivating β-oxygenation pathway in colorectal cancer. Int J Oncol. 46:1181–1191. 2015.PubMed/NCBI

16 

Edge S, Byrd DR, Compton CC, Fritz AG, Greene FL and Trotti A: AJCC Cancer Staging Handbook: From the AJCC Cancer Staging Manual. Springer; New York: 2011

17 

Miyo M, Yamamoto H, Konno M, Colvin H, Nishida N, Koseki J, Kawamoto K, Ogawa H, Hamabe A, Uemura M, et al: Tumour-suppressive function of SIRT4 in human colorectal cancer. Br J Cancer. 113:492–499. 2015. View Article : Google Scholar : PubMed/NCBI

18 

Nilsson R, Jain M, Madhusudhan N, Sheppard NG, Strittmatter L, Kampf C, Huang J, Asplund A and Mootha VK: Metabolic enzyme expression highlights a key role for MTHFD2 and the mitochondrial folate pathway in cancer. Nat Commun. 5:31282014. View Article : Google Scholar : PubMed/NCBI

19 

Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, Fantin VR, Jang HG, Jin S, Keenan MC, et al: Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 462:739–744. 2009. View Article : Google Scholar : PubMed/NCBI

20 

Jin S, Chen J, Chen L, Histen G, Lin Z, Gross S, Hixon J, Chen Y, Kung C, Chen Y, et al: ALDH2(E487K) mutation increases protein turnover and promotes murine hepatocarcinogenesis. Proc Natl Acad Sci USA. 112:9088–9093. 2015. View Article : Google Scholar : PubMed/NCBI

21 

Lehtinen L, Ketola K, Mäkelä R, Mpindi JP, Viitala M, Kallioniemi O and Iljin K: High-throughput RNAi screening for novel modulators of vimentin expression identifies MTHFD2 as a regulator of breast cancer cell migration and invasion. Oncotarget. 4:48–63. 2013.PubMed/NCBI

22 

Kim D, Fiske BP, Birsoy K, Freinkman E, Kami K, Possemato RL, Chudnovsky Y, Pacold ME, Chen WW, Cantor JR, et al: SHMT2 drives glioma cell survival in ischaemia but imposes a dependence on glycine clearance. Nature. 520:363–367. 2015. View Article : Google Scholar : PubMed/NCBI

23 

Ben-Sahra I, Hoxhaj G, Ricoult SJ, Asara JM and Manning BD: mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle. Science. 351:728–733. 2016. View Article : Google Scholar : PubMed/NCBI

24 

Csibi A, Fendt SM, Li C, Poulogiannis G, Choo AY, Chapski DJ, Jeong SM, Dempsey JM, Parkhitko A, Morrison T, et al: The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4. Cell. 153:840–854. 2013. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Miyo M, Konno M, Colvin H, Nishida N, Koseki J, Kawamoto K, Tsunekuni K, Nishimura J, Hata T, Takemasa I, Takemasa I, et al: The importance of mitochondrial folate enzymes in human colorectal cancer. Oncol Rep 37: 417-425, 2017.
APA
Miyo, M., Konno, M., Colvin, H., Nishida, N., Koseki, J., Kawamoto, K. ... Ishii, H. (2017). The importance of mitochondrial folate enzymes in human colorectal cancer. Oncology Reports, 37, 417-425. https://doi.org/10.3892/or.2016.5264
MLA
Miyo, M., Konno, M., Colvin, H., Nishida, N., Koseki, J., Kawamoto, K., Tsunekuni, K., Nishimura, J., Hata, T., Takemasa, I., Mizushima, T., Doki, Y., Mori, M., Ishii, H."The importance of mitochondrial folate enzymes in human colorectal cancer". Oncology Reports 37.1 (2017): 417-425.
Chicago
Miyo, M., Konno, M., Colvin, H., Nishida, N., Koseki, J., Kawamoto, K., Tsunekuni, K., Nishimura, J., Hata, T., Takemasa, I., Mizushima, T., Doki, Y., Mori, M., Ishii, H."The importance of mitochondrial folate enzymes in human colorectal cancer". Oncology Reports 37, no. 1 (2017): 417-425. https://doi.org/10.3892/or.2016.5264
Copy and paste a formatted citation
x
Spandidos Publications style
Miyo M, Konno M, Colvin H, Nishida N, Koseki J, Kawamoto K, Tsunekuni K, Nishimura J, Hata T, Takemasa I, Takemasa I, et al: The importance of mitochondrial folate enzymes in human colorectal cancer. Oncol Rep 37: 417-425, 2017.
APA
Miyo, M., Konno, M., Colvin, H., Nishida, N., Koseki, J., Kawamoto, K. ... Ishii, H. (2017). The importance of mitochondrial folate enzymes in human colorectal cancer. Oncology Reports, 37, 417-425. https://doi.org/10.3892/or.2016.5264
MLA
Miyo, M., Konno, M., Colvin, H., Nishida, N., Koseki, J., Kawamoto, K., Tsunekuni, K., Nishimura, J., Hata, T., Takemasa, I., Mizushima, T., Doki, Y., Mori, M., Ishii, H."The importance of mitochondrial folate enzymes in human colorectal cancer". Oncology Reports 37.1 (2017): 417-425.
Chicago
Miyo, M., Konno, M., Colvin, H., Nishida, N., Koseki, J., Kawamoto, K., Tsunekuni, K., Nishimura, J., Hata, T., Takemasa, I., Mizushima, T., Doki, Y., Mori, M., Ishii, H."The importance of mitochondrial folate enzymes in human colorectal cancer". Oncology Reports 37, no. 1 (2017): 417-425. https://doi.org/10.3892/or.2016.5264
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team